Systemic lupus erythematosus (SLE) is a chronic, multisystem human autoimmue disease characterized by the differentiation of short- and long-lived plasma cells (PCs) that secrete autoantibodies. Although the exact cause of SLE is unclear, environmental factors such as polyclonal B cell activation by bacterial and/or viral infection seem to play a significant role in the emergence of disease. In this case, it is anticipated that activated autoreactive B cells may participate in germinal center reaction and remain as memory cells long after infection, which may give rise to long-lived PCs secreting autoantibodies. We propose a hypothesis that memory B cells can differentiate into PCs only when receiving CD40/CD40L signals by antigen presentation to T cells. However, immunomodulatory factors such as CpG DNA may bypass this pathway, which potentially results in generation of autoreactive long-lived PC. We recently generated IA-B mice that lack MHC-II on about 95% of all B cells due to B-cell-restricted deletion of a loxP-flanked iab-neo allele by the cd19cre (Cre recombinase) transgene. Upon immunization with a T cell dependent antigen, a small number of antigen-specific MHC-II+ B cells in IA-B mice dramatically expand to differentiate into GC B cells and make normal levels of B220+ CD38+ memory B cells. However, these memory B cells lose MHC-II expression later because of ongoing deletion of MHC-II by the cd19cre transgene. In association with loss of MHC-II on memory B cells, IA-B mice showed impaired affinity maturation in long-lived PCs. With use of IAB mice, the specific aims to test our hypothesis are: 1) determination of the role of CD40/CD40L signal on memory B cell differentiation to long-lived PC by using IA-B mice carrying B cell specific CD40L transgene, and 2) determination of the effect of immunomodulatory factors that can bypass the requirement of MHC-II dependent antigen-presentation to T cells in long-lived PC differentiation. The outcome will provide a great help for understanding the development of autoreactive long-lived PCs and create new avenues for exploring therapy for SLE patients. [unreadable] [unreadable] [unreadable]